Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of
pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist
pregnenolone carbonitrile (
PCN) for 7 days. Analyses of mRNAs and
proteins in the supernatant, membrane, and cytosolic fractions of
enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchronous increase in mRNAs and
proteins involved in chemical
carcinogenesis and the response to
drug was possibly mediated by the PXR pathway and
proteasome core complex assembly was possibly mediated by the Nrf2 pathway. In addition, levels of
proteins in the endoplasmic reticulum lumen and involved in the
acute-phase response showed specific increase with no change in
mRNA level, and those composed of the mitochondrial inner membrane showed specific decrease. The analysis of phosphorylated
peptides of
poly(A) RNA binding proteins showed a decrease in phosphorylation, possibly by
casein kinase 2, which may be related to the regulation of
protein expression.
Proteins involved in
insulin signaling pathways showed an increase in phosphorylation, possibly by
protein kinase A, and those involved in apoptosis showed a decrease. Metabolomic analysis suggested the activation of the
pentose phosphate and anaerobic glycolysis pathways and the increase of
amino acid and
fatty acid levels, as occurs in the Warburg effect. In conclusion, the results of combined analyses suggest that PXR's effects are due to transcriptional and post-transcriptional regulation with alteration of nongenotoxic signaling pathways and energy homeostasis.